This invention relates generally to the field of powder characterization and more specifically to characterizing powders within powder beds using frequency-domain photon migration.
Accurate measurement of the characteristics of a powder bed such as the particle size or content uniformity of the powder bed are important in a number of areas. In the pharmaceutical and chemical industries, powder blending is often required to be accomplished properly to ensure product quality. For example, in the pharmaceutical industry, powder blend uniformity prior to tableting must be monitored to ensure the proper dosage of each tablet. Powder blending involves compression of an excipient material with an active ingredient. The blending of the excipient material and the smaller amount of the active ingredient is typically accomplished by rotating and vibrating blenders.
Particle segregation may occur based on differences in the size, density, charge, and/or shape of the particles. Particle segregation may result from over-blending, and may occur while transferring the powder between containers or while storing the powder. More importantly, the non-uniformity of a powder bed may result in segregation of an active ingredient. The uniformity of a powder bed, however, may be difficult to assess since both the excipient material and active ingredient are typically white powders.
Validation of blending operations and monitoring of blend uniformity in the pharmaceutical industry are regulated by the U.S. Food and Drug Administration, which requires measurements involving a validation study to assure future blending operations will provide a consistent blend. Yet, there are few methods for validation of blend uniformity with sampling and measurement errors within the tolerances set by the U.S. Food and Drug Administration. Continuous monitoring of blend uniformity within the blending and tableting processes could eliminate the need for validation studies, and would provide economical quality assurance of the operations. Evaluation of the uniformity of stored powder blends can ensure feedstock quality in many types of powder processing operations in the pharmaceutical, bulk, and specialty chemical industries.
One technique for assessing blend uniformity uses near-infrared spectroscopy (NIRS) to assess blend homogeneity from a differential absorbance spectrum of active ingredients. A sample is exposed to near-infrared light, and emitted attenuated light from the sample is detected. (See PCT Patent Application, Publication No. WO 01/22063 A1, entitled xe2x80x9cMethod and Apparatus for Spectrometric Analysis of Turbid, Pharmaceutical Samples,xe2x80x9d to Folestad, Josefson, Johansson.)
Laser induced fluorescence (LIF) measures weak fluorescence emissions originating from an active ingredient when excited by ultra-violet (UV) light. One drawback to the LIF technique is that it requires an optical window in a rotating blender and a synchronized light source and detector. Others drawbacks are that the effects of changing particle size can mask the fluorescence signals that could indicate blend content non-uniformity, and that there are many agents that do not provide a fluorescent signal.
The techniques of NIRS and LIF suffer from disadvantages. For example, the attenuation of light may be affected by changes in the absorption and scattering properties of a powder, but the NIR and LIF techniques cannot discriminate between changes in the absorption and scattering properties that are due to the presence of the active ingredient or to the size of the inert powder particles, respectively. Accordingly, the precision of measurements of uniformity may be insufficient.
In addition, the NIRS and LIF techniques interrogate a small volume of powder, which increases the variance of the measurement (See Muzzio, F. J.; Robinson, P.; Wightman, C.; Brone D. International Journal Pharmaceutics. 1997, 155, 153-178.) The complete random mixture model provides a theoretical prediction of the lowest possible measurement variance of a two component powder, as described by Equation (1):                               σ          2                =                                                            W                A                            ⁡                              (                                  1                  -                                      W                    A                                                  )                                      N                    ·                                    ρ              2                                      ρ              1                                                          (        1        )            
where WA is the weight percent of an active ingredient A, N is the number of particles of sample, xcfx811 is the density of active ingredients A, and xcfx812 is the density of the excipient material. For an optical probe, N is the ratio of sampled volume to mean single particle volume, as defined by Equation (2):                     N        =                                            V              sample                                                      V                _                            particle                                .                                    (        2        )            
According to Equation (1), for a low dose concentration, if the weight percent of active ingredient A is small, and if the sampled volume is small, the minimum variance is larger than for a higher dose concentration and a larger sampled volume. Since the NIR spectroscopy and LIF techniques can interrogate only relatively small samples, they may not provide satisfactory measurements for some low dose concentrations. Consequently, determining the characteristics of a powder has posed difficulties, especially in the pharmaceutical industry where powder bed uniformity is crucial and must be controlled.
In accordance with the present invention, disadvantages and problems associated with previous techniques for characterizing powder beds may be reduced or eliminated.
Characterizing a powder bed includes generating measurements by repeating the following. A location of the powder bed is illuminated with light having a time varying intensity with a resolution of less than one hundred nanoseconds. The particles scatter the light to alter the time varying intensity. The light propagates through a portion of the particles that defines a sampled volume. The light received from the powder bed is detected. The altered time-varying intensity of the light is measured to generate a time-dependent signal having a time-dependence that is less than or equal to a time-of-flight of a photon of the propagating light. An optical property is determined from the time-dependent signal, and a characteristic is determined from the optical property. The sampled volume is determined, and variance of the measurements is calculated. Uniformity of the powder bed is determined in accordance with the variance and the sampled volume.
Certain embodiments of the invention may provide one or more technical advantages. For example, according to one embodiment, a frequency-domain photon migration (FDPM) technique is used to obtain measurements of separate absorption and scattering properties of a powder bed. The measurements may be used to determine one or more characteristics of a powder bed, for example, the sizes of the particles of the powder bed, the concentration of an active agent, or the volume of powder being sampled. The measurements may be used to track changes of a characteristic of a powder bed undergoing blending, mixing, transfer, or storage.
Another technical advantage of one embodiment may be that an absorption coefficient and an isotropic scattering coefficient for a powder are obtained as separate parameters rather than a single product. The separate parameters allow for estimation of distinct characteristics describing of the powder bed uniformity, which may be used to detect downstream segregation effects and assess excipient uniformity.
Yet another technical advantage of one embodiment may be that larger volumes of powders, such as one to three times dosage weight as recommended by the Food and Drug Administration Good Manufacturing Practice guidelines, may be sampled. The larger sampled volumes, as compared to those of the NIRS and LIF techniques, yields a smaller natural variance for FDPM measurements. The smaller variance allows for a more precise assessment of blend uniformity, and enables evaluation of the uniformity of low dose powder blends. Accordingly, unlike other approaches, the embodiment may provide accurate measurement of low dosage formulations due to the separate determination of absorption and scattering properties and to the sampling of larger volumes.
Yet another technical advantage of one embodiment may be that a handheld or an in situ probe may be used to determine characteristics of a powder. A handheld probe may also be readily inserted into the powder, and an in situ probe may be used within a rotating or tumbling powder blender to provide convenient characterization of the powder. A probe may include circuits for miniaturization such as a chip sensor. Yet another technical advantage of one embodiment may be that the FDPM technique is self-calibrating. Yet another technical advantage of one embodiment may be that the measurements may be multiplexed using laser diode or light emitting diodes of various wavelengths. Yet another technical advantage of one embodiment may be that the technique does not require sampling or extraction of powder samples, reducing the increased variance owing to sampling practices.
Certain embodiments of the invention may include none, some, or all of the above technical advantages. One or more other technical advantages may be readily apparent to one skilled in the art from the figures, descriptions, and claims included herein.